New therapies are needed for brain tumors. Small molecule inhibitors of signal transduction pathways show great efficacy, but recent data suggest that their activity is often restricted to a sub-group of patients, based on the presence of mutations in the target protein (e.g., EGFR) or on the activity of associated pathways (for example, EGFR inhibitors work better in glioma when PTEN is intact). Therefore, a strong rationale remains for the development of more broadly active cytotoxic agents, particularly for use in combination with signal transduction inhibitors. Here we focus on a promising class of polynuclear platinum compounds (PPCs), and pursue strategies to enhance their activity by targeting and combining them with inhibitors in thePI3K pathway. In culture and preclinical models of glioma, PPCs show significantly greater efficacy and less toxicity than conventional platinums. Furthermore, they induce G2/M arrest and autophagy rather than apoptosis, despite triggering some of the same signal transduction pathways. Our lead compound is BBR3610, a spermine linker-based PPC, that is 250x more potent in suppressing clonogenicity of glioma cells than cisplatin. Here, we propose to study the mechanism of action and improve the efficacy of PPCs by: 1) enhancing the cellular response to PPCs by combining them with signal transduction inhibitors targeting PI3K, EGFR, mTOR and Raf; 2) improving delivery of PPCs to glioma by peptide-mediated targeting aimed at integrin and EGFR; and 3) investigate the synergy between PPCs and adenoviral therapy, using the Delta-24-RGD virus, based on the recent insight that DNA-damaging agents enhance oncolytic viral replication. It is our hypothesis that combining targeted PPCs with other therapies, such as oncolytic viruses and inhibitors of signal transduction pathways, represents an important opportunity to develop effective glioma therapies for the majority of patients. We are working with a team of experts in the fields of platinum chemistry, glioma therapy, drug development, peptide targeting, adenoviral therapy and biostatistics to accomplish our goals. PUBLIC HEALTH RELEVANCE: New treatments for glioma are needed. While much effort over the past decade has focused on highly specific inhibitors of signals that drive cancer cell growth, these have not fulfilled their promise in the clinic in the majority of cancers. We are proposing to investigate a new and promising family of cytotoxics, based on polynuclear platinum chemistry. The advantage of these agents is that they should work well with a broader spectrum of cancers as they target aspects of the cancer that are universal, such as proliferation. To reduce the disadvantages, which are toxic side due to effects on normal, healthy tissue, we are combining them with other agents and targeting them to the tumor. The goal is to devise a therapy capable of treating many different variants of cancer with an effective therapy.